Causes of Late Deaths After Pediatric Cardiac Surgery

A Population-Based Study

Statistical methods

Time-related mortality was assessed with survival analysis. Survival was calculated for all patients and separately for gender and diagnostic groups. The survival rate of patients operated on in different decades (1950s to 1980s) was also calculated separately to evaluate the progress of treatment. We compared the survival rates of different gender and decade groups and analyzed survival with and without non–CHD-related causes of death. The survival statistics were calculated with SURV3, the latest version of the survival analysis package developed at the Finnish Cancer Registry (12).

We compared each patient’s individual survival with that of the age-, gender-, and time-matched general population. For every patient and for every year of follow-up, we obtained the mortality of the general population. The expected probability of surviving 1 year was obtained for all individuals who, regardless of their survival status, were not censored before the beginning of the interval. We used the Hakulinen method (13) for combining the individual information with an estimate for the expected survival of the group.

The relative risk (RR) (with 95% confidence intervals [CIs]) analysis was used in evaluating the differences between observed versus expected numbers of deaths and between genders. If the CI of RR did not include 1.0, the difference was considered significant. Furthermore, the narrower the range of interval, the more significant was the difference.

The non–CHD-related causes of death of the patients were compared with the cause-specific mortality of the general population. The results appear as numbers of deaths observed and expected and as standardized mortality ratios (SMRs). The SMR expresses the ratio of observed causes of death to that expected on the basis of overall mortality rates in the general Finnish population. The expected numbers of deaths were standardized for age, gender, and time. The Poisson distribution was used to calculate the 95% CI. The significance of SMR was calculated with the approximation of Byar for the exact Poisson test (14).

Mode of CHD-related deaths

Most CHD-related deaths resulted from heart failure (158 of 397, 40%) (Table 1),which was the main mechanism of death in PDA, TGA, and UVH groups (Fig. 4).One-fourth (38 of 158) of the patients who died owing to heart failure had been previously diagnosed with pulmonary hypertension.

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Figure 4

Proportion of Modes of CHD-Related Death in Different Defect Groups

Perioperative = death within 30 days after second, third, or fourth operation. Numbers in blocksdefine the actual number of deaths in each group. Abbreviations as in Figures 1 and 2.

A total of 104 (26%) late CHD-related deaths resulted from a second, third, or fourth heart operation. The majority of perioperative deaths (54, 52%) occurred early (within 30 days) after the corrective operation among patients whose first operation had been palliative; 31 patients died early after re-operation, and 19 died after palliative surgery.

Surgery was the main mode of death among patients with TOF (20 of 60 deaths); 11 died early after the corrective operation, 7 after re-operation, and 2 after palliative operation.

Of the CHD-related deaths, 88 (22%) occurred suddenly. The mean age at sudden death was 19.3 years, whereas it ranged from 8.2 to 12.8 years in the other groups (Table 1). The vast majority of these patients had undergone corrective surgery (60 of 88, 68%). In most cases, sudden death resulted from arrhythmia, because no other reason for death could be found in postmortem examination (84%, 74 of 88 were examined). The majority of these patients had arrhythmias in their medical history. The other underlying causes of sudden death appear in Table 2.

Sudden death was the most common mode of death among patients with CoA (13 of 31, 42%) (Fig. 4). Of the 13 CoA patients who died suddenly, 5 (38%) exhibited untreated valvular aortic stenosis (AS). In 4 cases, the underlying cause was a ruptured or dissected aorta.

Among patients with TOF (18 of 60) and TGA (19 of 63), 30% of CHD-related deaths were sudden; 6% (15 of 246) of male patients with TOF and 10% (17 of 171) of male patients with TGA died suddenly. The proportion of sudden deaths among female patients was 2% in both groups (3 of 168, 2 of 171, respectively). The RR of sudden death for male patients was 3.4 (95% CI 1.004 to 11.6) in the TOF group and 4.3 (95% CI 1.02 to 18.3) in the TGA group. When these 2 diagnostic groups were combined, the RR of sudden death for male patients was 3.9 (95% CI 1.5 to 9.9).

The only death caused by anti-coagulation therapy was also sudden: 1 patient with an operated CoA and a prosthetic aortic valve died owing to subarcachnoidal bleeding. The patient’s treatment with warfarin was complicated by alcohol abuse.

Cardiovascular diseases related to congenital defects (Table 2) caused 46 (12%) deaths. In this subgroup, 3 diseases dominated: stroke (11 deaths), arrhythmia (6), and pulmonary emboli (6). Endocarditis caused 4 deaths, accounting for 1% of all CHD-related deaths. The overall incidence of lethal endocarditis was 0.07% (4 of 6,024). Two of these 4 patients had a bicuspic aortic valve, 1 exhibited re-coarctation, and 1 patient with UVH failed to recover from the Fontan operation. Brain abscess caused 4 deaths, 2 of which occurred among patients with pulmonary hypertension, and the other 2 patients had non-corrected cyanotic heart defects (TGA and TOF). Three patients died owing to myocardial infarct: 1 suffered from severe familial hypercholesterolemia (AS), 1 had anomalous coronary arteries (VSD+CoA), and 1 patient (CoA, AS, and Turner’s syndrome) had an occluded coronary artery. In 2 cases, the myocardial infarction was classified as non–CHD-related: the first involved a 44-year-old patient with operated CoA, severe diabetes with several complications, and a kidney transplant; and the second was a 36-year-old patient with operated PDA. Pulmonary hemorrhage was the cause of death of 2 patients, both of whom had Eisenmenger’s syndrome. In addition, 1 patient with Eisenmenger’s syndrome died suddenly due to massive acute pulmonary bleeding.

Causes of non–CHD-related deaths

The cause of death in 185 patients was unrelated to cardiac malformation. Diseases caused 127 deaths, and 58 deaths were violent. We found no differences between genders in the causes of non-CHD deaths.

The patients died of respiratory and neurological diseases significantly more often than did the general population (Table 3).Of the 17 respiratory deaths, 11 resulted from pneumonia in mentally retarded patients (6) and infants (5). The most common neurological causes of death were epilepsy (6) and meningitis (4).

The patients died in accidents less often than the general population. The number of accidental deaths was 28 in the patient population; the expected value was 44 (SMR 0.64, 95% CI 0.42 to 0.92).

The number of suicides was similar to the number expected. All 23 patients who committed suicide had undergone corrective surgery. The patients had undergone surgery at least 5 (mean 16.8) years before death (9 PDA, 3 CoA, 3 pulmonary stenosis [PS], 4 VSD, 3 ASD, 1 TOF). Two suicides were directly connected to heart defects: 1 ASD patient exhibited severe arrhythmias resistant to treatment, and 1 patient with PS took her own life rather than agree to another operation.

Mode of CHD-related deaths

The most common mode of CHD-related death was heart failure. Most of the patients with lethal heart failure had diagnosed pulmonary hypertension. Part of the late mortality could perhaps have been avoided with more careful follow-up and subsequent interventions, thus preventing the further rise of pulmonary resistance.

In our subjects, the number of late deaths due to surgery was high and resulted mainly from the patient’s subsequent corrective operation, whereas the follow-up began from the first—often palliative—operation (e.g., shunt in TOF).

Sudden death occurred most often in older patients with corrected heart defects and with known high risk of sudden death (18). The overall survival of patients with operated CoA was good: over 90% for 30 years. Yet the risk of sudden death was high. This obligates health professionals to ensure the careful follow-up and treatment of patients; the survivors of CoA repair are fixed, not cured (19).

Surprisingly, we discovered that male patients with corrected TOF and TGA died suddenly more often than female patients. The number of sudden deaths was small, and the significance of the difference was weak, but it existed nevertheless. When the 2 diagnostic groups were combined, the significance of the difference strengthened. Gender might be one of the fatal factors that contribute to sudden death in CHDs. Yet the causes of the difference need to be examined. This same kind of gender differences in sudden death has been published among adults with different heart diseases. For instance, male patients with coronary heart disease and male athletes die suddenly more often than female patients (9,20). In addition, the types of arrhythmias differ between men and women (8).

In the cardiovascular mode of CHD-related death, some data aroused our attention. The overall incidence of lethal endocarditis was only 0.07%. None of the deaths due to endocarditis occurred in patients with a valve prosthesis, although they are believed to carry a high risk for it (21). Yet, the other 2 patient groups at high risk for infective endocarditis were among our subjects: patients with aortic valve disease and cyanotic heart defect (21).

The number of deaths due to bleeding after anti-coagulation therapy was very low in our study, confirming the previously reported low incidence of fatal bleeding among young patients (22). When only mortality for endocarditis and bleeding is concerned, the artificial heart valve seems a safe alternative for young patients.

Previous studies have reported that patients with CoA are at high risk for death due to coronary disease and cerebrovascular accidents (1). Our findings, however, differed. Among the patients who underwent a successful operation for CoA (n = 887), only 1 death resulted from coronary heart disease. Even this death was classified as non–CHD-related, because of the patient’s severe diabetes and kidney transplant, which have been reported to increase one’s risk for all cardiovascular diseases (23). Moreover, only 1 of the patients died owing to a cerebrovascular accident; this death resulted from the combination of warfarin and alcohol. In earlier reports, a younger age at CoA repair has protected patients against lethal complications (1). Our study confirmed this, because all of our patients underwent surgery before their 15th birthday.

Unrelated deaths

The greatest difference between the patients and the general population appeared in the deaths caused by respiratory diseases. Most patients within this group died owing to pneumonia. High mortality due to pneumonia has often been connected to mental retardation (24) and seriously ill infants, as was the case in our study.

Neurological diseases caused a relatively high number of deaths. High mortality due to neurological causes partly resulted from other malformations and genetic syndromes with neurological disorders, which are quite common among patients with CHD. Some of the patients, however, suffered from brain damage caused by the heart defect itself or by cardiac surgery. Especially in the earlier days of cardiac surgery, cardiopulmonary bypass and related techniques, although enabling the repair of the heart itself, were not so gentle as to avoid potential brain damage entirely.

The number of accidental deaths was low. This might have resulted from the influence of parental over-protection, usually reported to cause only negative effects (25). One might also interpret this phenomenon as a reflection of the physical inability of the patients to engage in risky hobbies or hard physical work that could lead to accidental death. Alternatively, patients with a surgically corrected heart defect might appreciate life enough to avoid extreme hobbies and careless driving habits.

The number of suicides was equal to the number expected. This observation was in line with a previous study in which young adults with congenital heart disease assessed their emotional state as similar to that of the control population (26). In some studies, a severe physical illness has increased suicidal behavior (27,28), but in our study none of the patients with severe heart defect committed suicide. The 2 suicides connected to heart defects should warrant an offer of psychological assistance for patients with difficult health problems.